The hepatic monooxygenase system consisting of NADPH-cytochrome P-450 is involved in the oxidative metabolism of xenobiotics including therapeutic drugs, carcinogens, and environmental pollutants such as industrial wastes and pesticides as well as various endogenous compounds (steroids, fatty acids). The monooxygenase system is inducible by foreign compounds. This induction is apparent not only in increased amounts of the enzymes but also in dramatic alterations in the spectrum of monooxygenase activities catalyzed by the enzyme system. The objective of the studies outlined in this proposal is the characterization of the induction caused by exposure to the chlorinated pesticides, Mirex and Kepone. A study of the effects of these pesticides on the monooxygenase system assumes increased importance because of the persistence of these compounds in the environment and the accidental exposure of the human population which, in the case of Kepone, has resulted in disabling illness. Thus, the human population has experienced both chronic, low dose, and acute exposure to these agents. Experiments designed to characterize the effects of both types of exposure on the monooxygenase system are outlined in this proposal. Alteration of the activities catalyzed by this system could result in increases or decreases in the turnover of therapeutic drugs, hormonal changes, or increased malignacies due to an enhanced rate of carcinogen activation. In addition, since these pesticides are unlikely to be oxidatively metabolized by the enzymes they induce, opportunities to study alternative modes of metabolism, such as reductive dechlorination, as well as the molecular mechanism of the induction process exist.